Structure and Function of Paxillin

Paxillin 的结构和功能

• 批准号: 10396034
• 负责人: Christopher E Turner
• 金额: $ 40.5万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396034
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Address; Animal Model; Apical; Biological Models; Breast Epithelial Cells; Cell Polarity; Cells; Cellular biology; Centrosome; Communication; Cytoskeleton; Defect; Deposition; Development; Diabetes Mellitus; Disease; Disease Progression; Elements; Embryonic Development; Epithelial; Extracellular Matrix; F-Actin; Focal Adhesions; Funding; Goals; Golgi Apparatus; HDAC6 gene; Homeostasis; Intermediate Filaments; Intervention; Knockout Mice; Light; Malignant Neoplasms; Mediator of activation protein; Mesenchymal; Microtubules; Molecular; Morphogenesis; Organoids; Play; Positioning Attribute; Process; Regulation; Research; Resolution; Role; Scaffolding Protein; Signal Transduction; Structure; Time; Tissues; Vimentin; cell motility; developmental disease; imaging approach; knockout animal; migration; mouse model; novel; paxillin; polarized cell; programs; real-time images; trafficking

PROJECT SUMMARY The broad ongoing objective of this research program is to gain a deeper understanding of the fundamental mechanisms by which the focal adhesion adaptor/scaffold proteins paxillin and Hic-5 contribute to cell-matrix signaling and thereby control of cell polarity and migration in development and disease. Importantly, communication between the three elements of the cytoskeleton, the trafficking machinery and cell-matrix interactions is essential for establishing both apical-basal and front-rear migration polarity. However, our understanding of the key mechanisms coordinating and integrating these processes remains incomplete. Through our development of new paxillin and Hic-5 knock out mouse models, in combination with the use of various ex-vivo 1D, 2D and 3D cell matrix and organoid model systems and real time imaging approaches, we have identified new roles for paxillin in establishing epithelial and mesenchymal cell polarity, including regulation of centrosome and Golgi organization and microtubule stability via control of HDAC6 activity. We have also identified Hic-5 as a new mediator of F-actin-intermediate filament cross talk, mechanobiology and 3D extracellular matrix deposition and remodeling. Using these model systems in conjunction with quantitative real time confocal, light sheet and super resolution imaging approaches, the main goals that we will address in the upcoming funding period are- Goal 1: How does paxillin contribute to the regulation of polarized trafficking in directed mesenchymal cell migration? Goal 2: What is the role of paxillin in establishment of apical-basal polarity and in branching morphogenesis in mammary epithelial cells and Goal 3: How does Hic-5 regulate the vimentin intermediate filament cytoskeleton organization and function in motile cells and during epithelial-mesenchymal transition? Through the elucidation of these mechanisms we will be better positioned to develop rational approaches to disease intervention and to appreciate the basis of developmental disorders.

项目摘要 该研究计划的广泛持续目标是更深入地了解 焦点粘合剂/支架蛋白pa​​xillin和HIC-5的基本机制 有助于细胞基质信号传导，从而控制细胞极性和发育中的迁移和 疾病。重要的是，细胞骨架的三个要素之间的交流，贩运 机械和细胞矩阵相互作用对于建立顶端和前跑是必不可少的 迁移极性。但是，我们对协调和集成的关键机制的理解 这些过程仍然不完整。通过开发新的paxillin和HIC-5淘汰 鼠标模型，结合使用各种前体1D，2D和3D细胞基质和类器官 模型系统和实时成像方法，我们已经确定了paxillin的新角色 建立上皮和间质细胞极性，包括中心体和高尔基体的调节 通过控制HDAC6活性的组织和微管稳定性。我们还确定HIC-5是 F-肌动蛋白 - 中间丝横式谈话，机械生物学和3D细胞外基质的新介质 沉积和重塑。将这些模型系统与定量实时结合使用 共焦，轻纸和超级分辨率成像方法，我们将在 即将到来的资金期是 - 目标1：帕西林如何促进极化的调节 贩运定向间充质细胞迁移？目标2：Paxillin在建立中的作用是什么 顶端极性和乳腺上皮细胞的分支形态发生和目标3： HIC-5调节流动细胞中的波形蛋白中间细胞骨架组织和功能 在上皮 - 间质转变期间？通过阐明这些机制，我们将是 更好地制定理性的疾病干预方法，并欣赏 发育障碍。